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LAL-CL08 eCRF Completion Guidelines version 5.0_ 30Jan2018 of 66

LAL-CL08

Electronic Case Report Form Completion Guidelines

Investigational Product:

Protocol Title:

Protocol Code:

Version:

Version Date:

Information contained in this document is the confidential property of Alexion Pharmaceuticals, Inc. and any unauthorized use or disclosure of such information without the prior written authorization of Alexion Pharmaceuticals, Inc. is expressly prohibited. Further reproduction of this document in whole or in part is not permitted without the prior authorization of Alexion Pharmaceuticals, Inc..

Sebelipase alfa

A Phase 2, Open Label, Multicenter Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Sebelipase Alfa in Infants with Rapidly Progressive Lysosomal Acid Lipase Deficiency

LAL-CL08

5.0

30Jan2018


LAL-CL08 eCRF Completion Guidelines version 5.0_30 Jan 2018 of 66

Revision History / Scheduled Review Table

Version / Date Reason(s) for Change

1.1_29 March 2016 Database modifications:

Hematology:

-percentage results added for Neutrophils,

Lymphocytes, Monocytes, Eosinophils and Basophils

IMP admin page:

-reason for IMP administration change: the option “other “ has been added.

-target dose: 7,5 mg/kg dose has been added

2.0_ 23 March 2017 Synageva logo replaced with Alexion

Sections 7.13 through 7.20 added following clarification: Lab test required per protocol and performed outside of study visit window are to be entered as unscheduled visit and should be reported as AE if clinically significant.

Sections 7.36 and 7.37 minor clarifications on infusion stop time recording.

Procedures to be performed and entered in eCRF for Weeks from 145 to 156 added on relevant sections

3.0_ 23 May 2017 Section 5.2 SF subject- completion modification and CRA verification added

Section 5.4 Completed subject- screen shots of CRF page updated

Section 7.2 Abdominal MRI- number of visits updated in the header section and clarification from protocol added

Section 7.3 Abdominal ultrasound- - section updated Section 7.4 AEs- completion modification added related monitoring of AEs until f-up visit

Section 7.4 Adverse Events - section updated

Section 7.5 Concomitant medications- section updated

Section 7.8 End of treatment- section updated

Section 7.10 Inclusion criteria- section updated

Section 7.13 Coagulation panel- number of visits updated in



the header section

Section 7.14 Hematology- number of visits updated in the header section

Section 7.15 Chemistry- number of visits updated in the header section

Section 7.16 LFT- number of visits updated in the header section

Section 7.17 Urinalysis- number of visits updated in the header section

Section 7.18 Lipid Panel- number of visits updated in the header section

Section 7.19 Exploratory biomarkers- section updated

Section 7.20 ADA- number of visits updated in the header section

Section 7.25 Liver biopsy- number of visits updated in the header section

Section 7.27 Denver II- section updated

Section 7.28 Physical Examination- number of visits updated in the header section

Section 7.29 Physical Examination Lymphadenopathy- number of visits updated in the header section, additional updates added

Section 7.30 Physical Examination Abdominal photography- number of visits updated in the header section, additional updates added

Section 7.39 Concomitant procedures- section added with completion instruction

4.0_ 05 Sep 2017 Section 7.11.1 Autopsy Consent section added

Section 7.12 Survival Log section acdded

Section 7.17 LFT updated

Section 7.34 Study Completion updated

5.0_30 Jan 2018 Section 7.4 Adverse Events - section updated

Section 7.36 Enteral food Intake log – section updated



TABLE OF CONTENTS

1. General Information ............................................................................................................... 7

1.1. Abbreviation List ......................................................................................................... 7

1.2. eCRF Completion Guidelines ..................................................................................... 8

1.3. Clinical Database ........................................................................................................ 8

2. RAVE Navigation ................................................................................................................... 8

2.1. Login Procedure .......................................................................................................... 8

2.2. Password Resets and Locked Accounts ................................................................... 10

Support Center ............................................................................................................................ 10

2.3. Home Page ............................................................................................................... 12

2.4. Subject creation and selection .................................................................................. 13

2.5. Navigation between Forms ....................................................................................... 13

3. Data Entry Guidelines for All Forms .................................................................................... 14

3.1. General Instructions .................................................................................................. 14

3.2. Checkboxes/Drop Down Boxes ................................................................................ 14

3.3. Free Text Fields ........................................................................................................ 14

3.4. Data Entry ................................................................................................................. 14

3.5. Not Done – Entire Form ............................................................................................ 14

3.6. Date Format .............................................................................................................. 15

3.7. Time Format .............................................................................................................. 15

3.8. Unknown Data .......................................................................................................... 16

3.9. Data Corrections ....................................................................................................... 16

3.10. Audit Trail .................................................................................................................. 16

4. LAL-CL08 Visit Navigation ................................................................................................... 17

4.1. Visit Forms ................................................................................................................ 17

4.2. Cumulative Forms ..................................................................................................... 17

4.3. Creating Unscheduled Assessments ........................................................................ 17

5. Required Forms ................................................................................................................... 18

5.1. Screened Subject ...................................................................................................... 18

5.2. Screen Failed Subject ............................................................................................... 18

5.3. Enrolled Subject (receiving study drug) .................................................................... 19

5.4. Completed Subject .................................................................................................... 19

6. Query Guidelines ................................................................................................................. 20



6.1. Data Entry Errors (Non-conformant data) ................................................................. 21

6.2. Queries ..................................................................................................................... 21

6.3. Query Resolution ...................................................................................................... 21

7. Unique eCRFs ..................................................................................................................... 22

7.1. 12-Lead ECG (Screening, Clinically Indicated) ......................................................... 22

7.2. Abdominal MRI (Screening, Wk14, Wk24, Wk48, Wk 96, Wk144) ........................... 23

7.3. Abdominal ultrasound (Wk0, Wk12, Wk24, Wk48, Wk96, Wk144) ........................... 24

7.4. Adverse Events ......................................................................................................... 25

7.5. Concomitant Medication/Treatment .......................................................................... 29

7.6. Demography ............................................................................................................. 33

7.7. DNA Sample ............................................................................................................. 35

7.8. End of Treatment ...................................................................................................... 35

7.9. Anthropometrics (See protocol flow chart for Schedule of Assessments) ............... 36

7.10. Inclusion/Exclusion ................................................................................................... 37

7.11. Informed Consent ..................................................................................................... 38

7.11.1. Autopsy Consent ....................................................................................................... 38

7.12. Survival log ............................................................................................................... 39

7.13. Clinical laboratory Tests-LAL Enzyme (Screening)................................................... 39

7.14. Coagulation Panel (Screening, Wk 0, Wk 1, Wk 2, Wk 3, Wk 4, Wk 6, Wk 8, Wk 10, Wk 12, Wk 16, Wk 20, Wk24, every 2 months through Wk 48 and every 3 months thereafter, Wk156, Follow up/Early Withdrawal) ....................................................................................... 40

7.15. Hematology (Screening, Wk 0, Wk 1, Wk 2, Wk 3, Wk 4, Wk 6, Wk 8, Wk 10, Wk 12, Wk 16, Wk 20, Wk24, every 2 months through Wk 48 and every 3 months thereafter, Wk156, Follow up/Early Withdrawal ) ...................................................................................... 41

7.16. Chemistry (Screening, Wk 0, Wk 1, Wk 2, Wk 3, Wk 4, Wk 6, Wk 8, Wk 10, Wk 12, Wk 16, Wk 20, Wk24, every 2 months through Wk 48 and every 3 months thereafter, Wk156, Follow up/Early Withdrawal) .................................................................................................... 42

7.17. LFT (Screening, Wk 0, Wk 1, Wk 2, Wk 3, Wk 4, Wk 6, Wk 8, Wk 10, Wk 12, Wk 16, Wk 20, Wk24, every 2 months through Wk 48 and every 3 months thereafter, Wk156, Follow up/Early Withdrawal) ............................................................................................................... 43

7.18. Urinalysis (Screening, Wk 0, Wk 1, Wk 2, Wk 3, Wk 4, Wk 6, Wk 8, Wk 10, Wk 12, Wk 16, Wk 20, Wk24, every 2 months through Wk 48 and every 3 months thereafter, Wk156, Follow up/Early Withdrawal) .................................................................................................... 44

7.19. Lipid Panel (Screening, Wk 0, Wk 1, Wk 2, Wk 3, Wk 4, Wk 6, Wk 8, Wk 10, Wk 12, Wk 16, Wk 20, Wk24, every 2 months through Wk 48 and every 3 months thereafter, Wk156, Follow up/Early Withdrawal) .................................................................................................... 45

7.20. Exploratory biomarkers (Screening, Wk2, Wk 8, Wk 12, Wk 16, Wk24, every 6 months after Wk 24, Follow up/Early Withdrawal) ................................................................... 46



7.21. ADA (Screening, Wk 2, Wk 4, Wk8, Wk 12, Wk 16, Wk20, Wk24, every 3 months after Wk 24, Wk156, Follow-up/Early Withdrawal) .................................................................. 47

7.22. LALD Disease History - Screening ........................................................................... 47

7.23. LALD Disease History Enzyme Activity - Screening ................................................. 47

7.24. LALD Disease History Genetic Sequencing ............................................................. 48

7.25. LALD Disease History Other ..................................................................................... 48

7.26. Liver Biopsy (Wk48, Wk96, Wk144) ......................................................................... 48

7.27. Medical History ......................................................................................................... 49

7.28. Denver II (Screening, Wk 24, Wk48, Wk72, Wk96, Wk120, Wk144, Follow up/Early Withdrawal, Unscheduled) ...................................................................................................... 51

7.29. Physical Examination (Screening, Wk3, Wk9, Wk15, Wk20, Wk24, Wk36, Wk48, Wk60, Wk72, Wk84, Wk96, Wk108, Wk120, Wk132, Wk144, Wk156, Follow up/Early Withdrawal, Unscheduled) ...................................................................................................... 52

7.30. Physical Examination Lymphadenopathy (Screening, Wk3, Wk9, Wk15, Wk20, Wk24, Wk36, Wk48, Wk60, Wk72, Wk84, Wk96, Wk108, Wk120, Wk132, Wk144, Wk156, Follow up/Early Withdrawal, Unscheduled) ............................................................................. 53

7.31. Physical Examination abdominal photograpy (Screening, Wk3, Wk9, Wk15, Wk20, Wk24, Wk36, Wk48, Wk60, Wk72, Wk84, Wk96, Wk108, Wk120, Wk132, Wk144, Wk156, Follow up/Early Withdrawal, Unscheduled) ............................................................................. 54

7.32. PK Sampling (Wk0, Wk22, Wk 48) ........................................................................... 55

7.33. Family Medical History .............................................................................................. 55

7.34. Study Completion ...................................................................................................... 57

7.35. Transfusion ............................................................................................................... 59

7.36. Enteral food Intake log .............................................................................................. 59

7.37. IMP Admin ................................................................................................................ 60

7.38. IMP Admin Continued ............................................................................................... 61

7.39. Visit Date ................................................................................................................... 63

7.40. Vital Signs ................................................................................................................. 63

7.39 Concomitant Procedures ................................................................................................. 65

8.0 Investigator Signature ............................................................................................... 66



1. General Information

1.1. Abbreviation List

AATF Medidata Account Activation Training Form ADA Anty-drug Antibody AE Adverse Event CRA Clinical Research Associate/Monitor CS Clinically Significant CTCAE Common Terminology Criteria for AEs DM Data Management DNA Deoxyribonucleic acid ECG Electrocardiogram EDC Electronic Data Capture eCRF Electronic Case Report Form IAR Infusion-Associate Reaction LAL Lysosomal Acid Lipase LALD Lysosomal Acid Lipase Deficiency MedDRA Medical Dictionary for Regulatory Activities MH Medical History MRI Magnetic Resonance Imaging NCS Not Clinically Significant PI Principal Investigator PK Pharmacokinetics RAVE Medidata RAVE SAE Serious Adverse Event WFA Weight for Age WFH Weight-for-Height WFL Weight-for-Length



1.2. eCRF Completion Guidelines These eCRF Completion Guidelines describe all eCRF pages and how they should be completed. This manual does not describe how to use Medidata RAVE. For information on this, please refer to the RAVE Instruction Manual (click the “Help” link within RAVE).

1.3. Clinical Database The Electronic Data Capture (EDC) System, Medidata RAVE, is a web-based application that allows users to enter and manage electronic Case Report Forms (eCRF) via Microsoft’s Internet Explorer browser. RAVE will be used exclusively for this study as the method of capturing and updating subject study data in real time.

RAVE is a secure site and is strictly intended for use by individuals authorized by Alexion. For this reason, each person will be required to have a distinct password secured login to RAVE in order to access the LAL-CL08 study.

A CD-ROM for archival/storage of subject study data will be provided to each investigative site at the end of the study after the Clinical Study Report has been finalized. Until the CD is provided, the sites will have access to Rave in case eCRF access is necessary (e.g., for audit activity).

2. RAVE Navigation Site personnel are responsible for completing all tests, procedures, and for recording all background/ historical information required by the protocol. All fields on the eCRF should contain appropriate, complete, and accurate data. All items must be completed in full with every attempt made to obtain and record all data as requested.

All data for a visit should be entered in the eCRF within 5 days of the clinic visit. It is possible to have multiple sessions of RAVE open in order to complete related forms.

2.1. Login Procedure

Access to Medidata is limited only to authorized users. A username and password is unique to each user and must not be shared or made available to any other user. To log in to Medidata RAVE, navigate to https://ppd-synageva.mdsol.com. A computer with internet browser (Chrome, Firefox, Internet Explorer, or Safari) and an active high-speed internet connection are required to access the Rave application. If you are utilizing Internet Explorer 10 and Medidata Rave is not operating correctly, contact the Medidata Rave Helpdesk for assistance.

Access can be obtained through your PPD monitor/CRA. The following information will be needed:

First Name Last Name

Site # PI Name Phone Number Unique email address (only accessed by one person)

Date of your previous training for RAVE, if you have already used the system for other studies



Users will receive one email from Medidata. This email will contain an activation code (From:[email protected] [mailto:[email protected]]) and instructions for account activation. Please note, this email may be sent to a junk or spam email folder. Check these folders if the email is not received in a timely manner.

Browser address line: https://ppd-synageva.mdsol.com

An email will be sent with a link to activate your account and a separate email which includes your PIN for activation. The user name is assigned automatically (a combination of the first initial and the last name); however, you will be allowed to create your own password after activation. You will also be asked to provide answers to security questions. Please note the activation email link will expire in 14 days. If your email activation expires, please contact Medidata Customer support.

Note: If a message is received asking if Windows should save the password for future use, always click “NO” in order to ensure data security.

If the user has not trained in RAVE previously or if their previous training is out-of-date, the system will provide eLearning modules on the user’s Medidata RAVE home page. The user must complete all eLearning before the system will allow the user to access the Synageva LAL-CL08 database. Users that are already trained in RAVE will be prompted to complete a short refreshement assessment.

The login procedure will give each user personal access to only those protocols which they have been granted access following completion of Rave Training.

The login procedure will give users access to the protocol and subjects’ forms applicable to data collection for the subjects enrolled at their specific site.

To ensure data security, log off and close the internet browser screen before stepping away from the computer.

Upon logging in, the application will display the Rave Home page.



2.2. Password Resets and Locked Accounts If your account has been locked or you have forgotten your password, go to http://tollfree.mdsol.com/ and call the Medidata Help Desk number appropriate for your region. Alternatively, click “Forgot Password?” on the log-in screen and follow the directions provided. Retain your PIN number from the initial activation as you will need this to use the Forgot Password link.

Support Center If you have technical questions about the Medidata Rave application or need customer support, please contact the Customer Service Center at Medidata Solutions, Inc. You may contact Medidata via email or

phone:

Global Help Desk

Toll Free * 001-866-MEDIDATA (633-4328)

* Please be advised that our Toll-Free menu has been updated to include “Assistance by Product”. After dialing the Toll-Free number, you may select one of the following product options:

1= Rave 2= iMedidata 3= CTMS 4= Balance 5= Monitor 6= Insights 7= Coder 8= Designer 9= Grants Manager Planning & CRO Contractor 0= General inquiry *= Fax

Direct 001-973-659-6780

Fax 001-973-954-5621

Toll-Free Fax 001-877-743-2350



E-mail [email protected]

Hours 24 hours a day, 7 days a week

Supported Languages English, French, Spanish, Italian, German

APAC Help Desk

Toll-Free 0120-543-675

Fax +81-3-67434010

E-mail [email protected]; [email protected]

Hours

Mon - Fri Japan Users - 8:00 AM to 9:00 PM JST China Users - 9:00 AM to 9:00 PM JST Korea Users - 8:00 AM to 6:00 PM JST

Supported Languages Japanese, Mandarin, Korean

World Wide Toll-Free Numbers

Country Toll-Free Number

Australia 1 800 186 549

Belgium 0800 49 414

Brazil 800 891 4809

Canada 1 866 232 9966

Croatia 0800 222 879

Denmark 80 883736

Germany 0800 000 1527

Italy 800 987 161

Mexico 001 866 3562083

Netherlands 0800 949 4567

Russia 8 10 8002 7803011

Spain 800 098 040

Turkey 00800 1420 31101

UK 0800 001 5212

US – Direct 1 973 659 6780

US – Fax 1 973 954 5621

US - Toll-Free 866 633 4328

US - Toll-Free Fax 877 743 2350



2.3. Home Page The home page is used to select the appropriate site and subject. If you have access to more than one site, select the site number and the subject numbers attached to your site will appear. If you only have access to one site, your list of subjects is displayed, as shown below.

1. Left side: Installed Modules: reports available to you Last 10 Subjects Resources: PPD Internet Site

2. Center: Subject List of Subjects Icon Key: click to view in a separate window

3. Right Side:

Task Summary: list of tasks that need to be performed based on your role in the study



2.4. Subject creation and selection

Site will be responsible for populating the sequential subject number per site.

How to add a new subject:

1.Navigate to Site Home Page.

2. Click Add Subject.

3. Enter sequential subject number in AAAAXXX format where AAAA is the site number and XXX is the sequentially assigned subject number and click Save.

If you can’t see the “add subject” button please contact your CRA.

Once the subject is created, There are 3 ways to select a subject in RAVE:

1. Last 10 Subjects 2. Advanced Search 3. Subject List

To enter or edit data for a particular subject, click on the appropriate subject number or enter the subject number in the search box.

2.5. Navigation between Forms After choosing a subject from the list, click on a Folder from the visit list located on the left hand side of the window to begin entering subject data. When navigating in Rave DO NOT use the back button on the internet browser. Navigation tabs are used to navigate within the system. These tabs are located directly above the main area.



3. Data Entry Guidelines for All Forms

3.1. General Instructions

The following are general completion guidelines which should be followed by the site personnel. Always contact your CRA for study specific questions such as eCRF completion or clinical/protocol questions.

All Medidata entries must have corresponding adequate source documentation, which accurately supports all electronic Case Report Form (eCRF) data.

3.2. Checkboxes/Drop Down Boxes

Any of the methods below may be used to populate a checkbox/radio button:

Navigate to the checkbox/drop down boxes using the mouse and left click.

Navigate to the checkbox/drop down boxes using the TAB key and press Enter or the Space bar.

3.3. Free Text Fields

Some fields allow data to be typed in. Text is not case sensitive and is automatically converted to upper case. Free text fields are limited to 198 characters including spacing.

In a Comment Field or Other Field, you can copy and paste text from another field.

3.4. Data Entry

eCRFs are completed for all screened and screen failed subjects.

eCRFs should be completed within 5 business days of each subject visit, however, under special circumstances, such as database lock or DSMB Meetings, the monitor may ask for a faster turnaround time. Any change of timelines will be communicated to the site in advance.

Data needs to be entered into Medidata in English, with no special characters, symbols or non-English language.

All eCRF entries must have corresponding adequate source documentation that accurately supports all eCRF data.

3.5. Not Done – Entire Form If an assessment was not done, select Not Done, where available, at the top of the page and save the page. No additional information is required on the page.

Note: There are a few forms that are required for all subjects. These forms do not have a Not Done check box:



Visit Date Informed Consent Demography Inclusion/Exclusion Medical History- Screening LALD Disease History – Screening Vital Signs All the forms that ask if procedures have been performed or not (Family Medical History Y/N,

Clinical Laboratory tests Y/N, 12-lead ECG Y/N, Physical exam Y/N, Physical examination abdominal photographs Y/N, Abdominal MRI Y/N, Denver II Y/N , Adverse Events Y/N,Concomitant Medications Y/N)

3.6. Date Format Dates must be recorded in the International Date Format (Day/Month/Year, dd/MMM/yyyy). For the Month, the first 3 letters of the month are provided in the drop-down box. For example, January 30, 2012 is recorded as 30/JAN/2012. Most dates in the database must be a complete date. It is expected that complete dates will be entered, whenever possible.

Partial dates are only acceptable on the following forms:

Medical history Family Medical History LALD Disease History – Screening Concomitant Medications Start Date (medications started after screening should have complete

dates)

Concomitant Procedures

If any part of the date is unknown, please use the following formats:

Day: UN

Month: UNK

Year: Year must never be unknown and should be entered.

Example: UN/UNK/2015

If only a partial date is known, the site should then enter UN for a missing day and UNK for a missing month (UN-UNK-2015). The year will never be accepted as unknown, A non-conformant system query will fire where an incomplete or unknown date (for all other CRFs not listed above) is entered. In those instances, the query should be closed with an explanation or confirmation of the incomplete date entered.

3.7. Time Format All times must be recorded using a 24 hour clock (00:00 – 23:59) format. For example, 1:30 pm would be recorded as 13:30. Do not use 24:00; midnight is recorded as 00:00 for the following day.

Time is always expected, a non-conformant query will fire if UN:UN is entered.

If time is not known, answer the query stating that the time is unknown.

In some cases unknown times are acceptable. For those forms then an unknown checkbox will be present.



3.8. Unknown Data If data are unknown, not applicable, or not available, please leave the field blank. Enter a comment in the comment field (see section 4.6) to explain why the data is not known. If a query is generated because the field is required, confirm that the data is unknown, not applicable, or not available in the query resolution.

Please note that there may be data fields that have ‘Not Done’ available; if the test or procedure was not done, please select this option and leave the rest of the row blank.

3.9. Data Corrections Corrections to the data can be made at any time until the entire study database is locked. The data points will be locked after each form is completed by the site, monitored by the CRA, and reviewed/queried by DM. Every correction must have a reason recorded as to why the correction was made. Corrections will be tracked in Rave by user name, date and time.

If corrections are necessary after the data point or form has been locked (but prior to study database lock), a request can be made through the assigned CRA to unlock the data point or form(s).

3.10. Audit Trail The audit trail can be seen by clicking on the status icon. The audit trail page will open with a text box.



4. LAL-CL08 Visit Navigation

4.1. Visit Forms eCRF pages are organized into folders by study visit (excluding the cumulative forms as defined in Section 4.2 below). Each section includes the required eCRFs for that study visit. The study visits are:

Screening Week 0, Week 1, Week 2, etc. through Week 156 Follow up/Early Withdrawal Autopsy Consent Survival Log Unscheduled visit(s)

4.2. Cumulative Forms Cumulative eCRFs collect data throughout the study and are not scheduled a as part of any specific study visit. These forms should be reviewed at each visit. Data should be updated and new data should be entered if new/updated data is available.

The cumulative forms include:

Adverse Events Concomitant Medications/Treatments Concomitant Procedures Transfusion Enteral Food Intake Log

4.3. Creating Unscheduled Assessments From the subject’s home page, selecting Unscheduled Event from the “Add Event” drop down will add an Unscheduled visit in a new Unscheduled Visit folder.



Enter visit date on Visit Date page and check each unscheduled assessment performed on the Unscheduled Assessments page.

Click “save” to allow the relevant pages to appear for each assessment selected.

5. Required Forms

5.1. Screened Subject A subject is considered a screened subject when they sign Informed Consent Form (ICF).

5.2. Screen Failed Subject A subject is considered a screen failure if s/he provided Informed Consent and either does not meet the eligibility criteria, or the subject decided to withdraw consent prior to any protocol assessments being conducted. Screened subjects who do not meet eligibility should not be entered in the database.

The following set of eCRFs must be completed for subjects that are Screen Failed.

Screening o Visit Date o Informed Consent/Assent o Inclusion/Exclusion Criteria o Demography o Family Medical History

Adverse Events (if an SAE led to Screen Failure, enter the SAE)



Study Completion Page (Follow up/early withdrawal)

All data available from the screening visit may be entered in EDC even if it is not part of one of the required forms above. Data management will inactivate any blank non-required forms.

5.3. Enrolled Subject (receiving study drug)

Subjects that meet eligibility criteria and are enrolled into the study will have all data entered in the corresponding eCRFs. Each folder includes the required eCRFs for that study visit. If a subject rescreened for the study, the most recent data that was used to assess the subjects’seligibility should be entered in the Screening folder.

For early termination subjects, all data up until the point at which they discontinued the study should entered.

The End of Treatment and Study Completion pages in the Follow up/Early Withdrawal folder are required for all enrolled subjects.

5.4. Completed Subject Enter all visits that were completed by the subject. Ensure that the End of Treatment and Study Completion pages in the Follow up/early withdrawal folder are completed.



6. Query Guidelines

A query is a question/issue/problem with eCRF data that needs clarification. Queries may be created on a single data field or on a section within an eCRF. A query can be created automatically by the system (System Generated query) or manually by a user, CRA, DM, or Safety (User Generated query).

Following these eCRF Completion Guidelines will help to minimize the number of queries generated.

Queries should be resolved within 3 business days of being generated. It is important to review data on a regular basis. Guidelines for responding to discrepancies are noted below.

A System Generated query alerts the user there may be a problem with a single response or a group of responses. This may be related to the data capture or missing data. System generated discrepancies are automatically created during data capture, immediately after data is saved or after data management runs a batch validation procedure on the study database.

A User Generated query is the result of someone else, such as CRA, DM, or Safety, creating a manual discrepancy based on Source Data Validation/Review.

For Queries Created During Data Entry:

If applicable, correct the data immediately and the discrepancy will automatically close. No other action is required.

If the data entered is discrepant (e.g. out of range value that does not affect subject eligibility to participate in the study), answer to the query confirming that the data is correct and add an explanation in the comments field is required.

For Queries Created After Data Entry:

Change the data immediately. If the new data is no longer discrepant, the query will automatically close after the eCRF is saved or batch validated.

If the value is blank because of an unknown date or missed procedure, or if the data is discrepant but correct, (e.g. out of range value that does not affect subject eligibility to participate in the study), an explanation in the comments field is required.



6.1. Data Entry Errors (Non-conformant data) Entry errors are identified with this icon:

Queries will appear after a form is saved if the data entered on the form does not meet field requirements (i.e., future date, out of range value, or blank field). The data must be corrected.

Examples of not conformant data are:

Mixed letter and number data entry into a number only field Adding text to a number only field Periods or other punctuation (e.g.: >, or <, or commas) Forcing an ‘incomplete date’ in a date field that must be complete. For example, typing ‘UNK’ into

a Month field where UNK is not in the dropdown field. Entering an incomplete time in a required time field.

6.2. Queries Queries are identified with the following icons:

The RAVE Home page Task Summary will display “Query Open” with the current number of open queries for all subjects. If there are no open queries, the number will be “0”. Select the arrow to the left of “Open Queries” to view subjects with open queries. If you have selected a particular subject, clicking the arrow to the left of “Open Queries” will display the forms that contain open queries.

Since the EDC system is in “real time”, the Query Open number may change frequently during the course of a day.

6.3. Query Resolution Select an open query that needs to be addressed by clicking on the query. Modify or confirm the data listed in the query.

o If a change to the data is not necessary, add a comment to the response box stating that the data is correct as is. Select the “Save” button.

o if a change to the data is necessary correct the data. The query response box will grey out if data has been modified. Select the “Save” button. An “Audit Resolution” page will appear. Enter a reason for the data change.



If the query is generated by the system and the data is updated so that the query is no longer applicable, the query will automatically close when the form is saved.

If the query is generated by the study team, either a Clinical Research Associate (CRA) or a Clinical Data Associate (CDA) will review the query response. If the reviewer accepts the change(s) to the data as a result of a query, the query will be “closed”. If the data is still in question, the CRA/CDA will re-open the query. These queries should be resolved only after the subject’s source documentation has been reviewed by the CRA.

7. Unique eCRFs

7.1. 12-Lead ECG (Screening, Clinically Indicated) 12-Lead Electrocardiogram

Field/Question Instructions

Was ECG performed?

If No o Select the No Radio button o Save the form

If Yes o Select the Yes Radio button and proceed to complete the entire form

Date ECG performed Enter a complete date (dd MMM yyyy). A partial/unknown date is not allowed.




Investigator Interpretation

Screening

Enter the PI’s assessment of the ECG results, choosing the applicable radio button. Normal Abnormal – Not Clinically Significant Abnormal – Clinically Significant

If Abnormal CS is selected record the cause of the abnormality on the Medical History form. All visits other than Screening

Enter the PI’s assessment of the ECG results, choosing the applicable radio button. Normal Abnormal – Not Clinically Significant Change Abnormal – Clinically Significant Change from Baseline

If Abnormal CS Change From Baseline is selected, record the cause of the abnormality as an Adverse Event.

7.2. Abdominal MRI (Screening, Wk14, Wk24, Wk48, Wk 96, Wk144)

Abdominal MRI should be considered in subjects receiving general anesthesia and/or sedation for other procedures at the indicated timepoints.

The Screening MRI may be obtained up to 8 weeks of treatment. The MRI may be conducted at any time from Week 24 through Week 32, and then Annually (at w48, w96 and w144) Abdominal MRI must be done at week 144. Week 156 is optional and can be marked as Not

Done. However, if for any reason week 144 assessment was not done then ensure week 156 assessment gets done.

There should be at least 3 months between each MRI. (Either a MRI or Ultrasound should be performed at a given timepoint.)

The MRI will be performed up to 6 times during the course of the study.


Was abdominal MRI

performed?

If No o Select the No Radio button and specify reason If Yes o Select the Yes Radio button o Also enter:

o Date abdominal MRI performed




Abdominal MRI: Date abdominal MRI performed

Enter a complete date (dd MMM yyyy). A partial/unknown date is not allowed.

7.3. Abdominal ultrasound (Wk0, Wk12, Wk24, Wk48, Wk96, Wk144)

CRF page at week 156 contains Abdominal ultrasound folder but collection is not required at week 156. Please respond NO when you open the page.


Was abdominal ultrasound performed?

If No o Select the No Radio button and specify reason If Yes o Select the Yes Radio button o Also enter:

o Date abdominal MRI performed o interpretation o liver volume o spleen volume

Date abdominal ultrasound performed

Enter a complete date (dd MMM yyyy). A partial/unknown date is not allowed.

Interpretation Select appropriate radio button: Normal Abnormal Not clinically significant Abnormal clinically significant If Abnormal CS is selected: • Record the cause of the abnormality on the Medical History form (Wk0) or as an adverse event (all other visits except Wk0). All visits other than Screening

Liver volume Enter Liver volume in cm3

Spleen volume Enter Spleen volume in cm3



7.4. Adverse Events

Enter any new signs and symptoms or worsening of baseline conditions experienced by the subject from the time of consent until completion of the follow-up phone call at approximately 4 weeks after the last dose of study drug administered under this protocol. Refer to section 7 of the protocol for additional guidelines for assessment and recording of Adverse Events, abnormal laboratory tests, and Medical Events of Interest. Frequency, severity, duration, initiation of or changes in treatment, and outcome are some descriptors used to determine whether or not a chronic and/or recurrent condition/symptom meets the criterion of an AE. It is the responsibility of the Investigator to determine whether changes in any of these descriptors are significantly different (indicative of worsening) when compared to baseline to warrant recording of an AE. Notes:

All lab values that are indicated as a clinically significant change from baseline must be captured as an AE.

LAL Deficiency disease related findings and out of range lab values at screening are to be part of the medical history with a comment indicating they are related to underlying LAL Deficiency.

If an SAE was reported by the site to the safety group (should be done within 24 hours from acknowledgement), the event must be recorded on this form in Rave with identical details. “Is AE Serious?” should be marked Yes.

Do not re-list events that were reported at previous visits if there is no change If an event changes in severity only the highest severity should be recorded. A new adverse

event line should not be entered. For example, if low back pain is an event that started as mild on 11-Jan-13 and became moderate on 13-Jan-13 and the low back pain stopped on 15-Jan-13, please record the following:

o One event of low back pain o Start date = 11-Jan-13 o Severity = moderate o Stop date of 15-Jan-13.

Do NOT report procedures as AE; report the events for which the procedures were performed. Record all procedures on the Concomitant Procedures page.

Do NOT report death as an AE; report the primary cause of death. The AE(s) that resulted in death should have the outcome noted as “fatal” and the end date as

the date of death (this event must be noted as a “serious” adverse event.). AEs that are not the cause of death should have the outcome as “ ongoing”. The end date should remain blank with “ongoing” checked.

Do NOT report two terms as one AE, terms should be split, or only one diagnosis listed: “Fall due to loss of balance” should be reported as “Fall” and “Loss of Balance”; Worsening of spasticity due to medullar ischemia” should be reported as “Worsening of spasticity” and “medullar ischemia”;

Record one diagnosis rather than separate entries for each sign/symptom of the diagnosis, when the diagnosis is known. If the diagnosis is unknown, record each sign/symptom as unique AEs

If an condition present in medical history worsens create a new AE with “Worsening” added to the event term.

o Do not record improving Adverse Events. o Keep the greatest severity AE open until the AE has completely resolved.

All AEs up until the date of the follow-up visit should be recorded in eCRF.

If adverse event occurred between last sudy visit (last IP infusion) and f-up visit and is related to the IP infusion received outside of the study (commercial product receipt or compassionate use receipt), all AEs should be documented in the source notes and in the eCRF ( AE section).




Did the subject experience any adverse events?

If No o Select the No Radio button

If Yes o Select the Yes Radio button o Also enter:

o Adverse Event o Start Date o Start Time o Start time unknown (if applicable) o End Date o End Time o End time unknown (if applicable)

o Is AE Serious o Is AE an infusion associate reaction? o Severity/Intensity o Outcome o Relationship to IMP o IMP action taken o Other action taken

Adverse Event Enter the AE diagnosis/syndrome name into the text field. A response longer than 100 characters, including spaces, will result in an error message. Do NOT enter abbreviations, e.g. CAD, HA, CHF. Include location if appropriate (e.g. Right arm fracture).

Start Date Enter a complete date (dd MMM yyyy). A partial/unknown date is not allowed.

Start Time Unknown times are allowed if the Start Date is not the same as a Study Drug Infusion date. In case time of AE is unknown the checkbox “start time unknown” is to be checked If the AE occurs on the day of the infusion, a full start time is expected to be recorded.

End Date If AE has stopped, enter a complete date (dd MMM yyyy). A partial/unknown date is not allowed.

End Time If End Date is entered, enter the time. Unknown times are allowed on non-study drug dates. In case time of AE is unknown the checkbox “end time unkown” is to be checked If the AE stops on the day of the infusion, a full stop time is expected to be recorded.




Is AE serious? If No Select the No Radio button

If Yes Check all of the appropriate items listed below Death Immediately Life-threatening Hospitalization or prolongation of existing hospitalization Congenital Anomaly/Birth Defect Persistent or significant disability or incapacity Important Medical Event The data in Rave must match the data reported to safety on the SAE/IAR form.

Is AE an infusion associated reaction?

If No Select the No Radio button Proceed to the Severity/Intensity question

If Yes Select the Yes Radio button Proceed to the Severity/Intensity question

The data in Rave must match the data reported to safety on the SAE/IAR form.Severity/Intensity Utilize the drop down list to select one of the following:

Mild: A type of AE that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not generally interfere with usual activities of daily living.

Moderate: A type of AE that is usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort, but poses no significant or permanent risk of harm to the research participant.

Severe: A type of AE that interrupts usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention.

Adverse Events are to be collapsed into maximum severity and not reported separately for any change (increase/decrease) in severity

Outcome Utilize the drop down list to select one of the following: Fatal Not recovered/Not resolved Recovered/Resolved with Sequelae Recovered/Resolved Ongoing Other Unknown




Relationship to IMP Utilize the drop down list to select one of the following: Related: Reasonable temporal relationship of the clinical event to study drug

administration AND cannot be reasonably explained by other factors (such as the subject’s clinical state, concomitant therapy, and/or other interventions).

Possibly related: The temporal relationship of the clinical event to study drug administration makes causal relationship possible but not unlikely AND other drugs, therapeutic interventions, or underlying conditions do not provide a sufficient explanation for the observed event.

Unlikely related: The temporal relationship of the clinical event to study drug administration makes causal relationship unlikely but not impossible AND other drugs, therapeutic interventions, or underlying conditions provide a plausible explanation for the observed event.

Not related: Data are available to clearly identify an alternative cause for the reaction (e.g., antigen in the case of suspected drug-induced hepatitis, hemorrhage due to mechanical injury).

IMP action taken Utilize the drop down list to select one of the following actions to IMP that resulted from an adverse event. Ensure that the action you indicate is also recorded on the study drug infusion page. Dose increased- – used to indicate that the study drug schedule was modified

to increase the dose; either by changing the frequency (eg, qow to qw) or amount (eg, 1 mg/kg to 3 mg/kg).

Not changed Dose reduced - used to indicate that the study drug schedule was modified to

reduce the dose; either by changing the frequency (eg, qw to qow) or amount (eg, 1 mg/kg to 0.35 mg/kg).

Infusion interrupted - used to indicate when an infusion had to be temporarily stopped for whatever reason and then was restarted

Infusion stopped – only use this to indicate when an infusion is stopped before the full volume is administered and not restarted, but subsequent infusions occurred. If no further infusions occurred then use the code “Study Drug Permanently Discontinued”

Study drug withheld – used ot indicate that the study drug schedule was modified by temporarily not administering the regimen of medication for a single infusion or multiple infusions (eg, week 5 dose not given due to an adverse event)

Study Drug Permanently Discontinued – used to indicate that study drug schedule was stopped permanently. IMPORTANT NOTE: The End of Treatment page and the Study Completion page should indicate that the reason for ending treatment was because of an adverse event.

Rate changed – used to indicate that the infusion was slowed down as a result of the adverse event (eg, rate reduced to 50% as a result of an IAR). if the rate was increased following to an AE, please consult your monitor

Other Not applicable –impact to the study drug is not relevant because of this

adverse event (eg, single occurrence of a headache on a non-dosing day that did not impact the dosing regimen)




Other action taken Utilize the drop down list to select one of the following: None ConMed Non-drug Therapy/procedure Hospitalization Other If “Other” is selected you will need to specify more details. A response longer than 100 characters, including spaces, will result in an error message

7.5. Concomitant Medication/Treatment Notes: Enter all of the following in the Concomitant Medication form.

All medications and treatments taken after the Informed Consent is signed through completion of the follow-up visit (approximately 30 days after the last dose of IMP)

Medications and treatments taken during the study until the subject completes the Follow-up call or a minimum of 4 weeks from the date of last dose).

If a dose/frequency/route is modified, the end date should be entered for the current record and a new record added with the new dose/route recorded.

Do NOT record medication/treatments that were prescribed but were not taken by the subject. In case of Concomitant medications prescribed to be taken more than once per day enter the CM

only once in eCRF even if on the first or last day of the administration the subject has actually not taken all the foreseen docses) (eg drug prescribed to be takne 3 times per day and only 1 or 2 of them taken on first day of treatment due to time of prescription)

If subject experienced any AEs between F-up Visit and last study visit ( last IP infusion), concomitant medications taken by the subject should be recorded in the source notes and in the eCRF.

Additionally, if subject received IP infusion outside of the study (commercial product receipt or compassionate use receipt) between last sudy visit (last IP infusion) and f-up visit , the IP receipt should be recorded in the eCRF.




Did the subject receive any medications or treatments within the timeframes specified in the protocol?

If No o Select the No Radio button. o Save the form.

If a Concomitant Medication or Treatment does occur, change to “Yes” and save the form.

If Yes o Select the Yes Radio button. o Also enter:

o Medication/Therapy Name o Reason for use o Start Date o End Date o Ongoing? (check if yes) o Dose o Units o Route o Frequency

Medication/Therapy Name

Enter the generic name into the text field. If several Medications are taken at the same time, each Medication should be

listed as a separate entry. For combination drugs (e.g., Tylenol Sinus) record the generic names of each

component as separate entries. All vitamins, supplements and herbals treatments should be captured in

addition to medications used to treat medical history conditions and adverse events.

Do not enter abbreviations, routes, dosage, or utilize special characters. A response longer than 100 characters, including spaces, will result in an error message.

Names may be queried for clarification if misspelled or entered in a language other than English.

Reason for use Type the reason this medication/treatment was taken into the text field. A response longer than 100 characters, including spaces, will result in an error message.

For all medications or treatments received during the course of the study, the reason should be recorded on the Medical History, Adverse Event or LALD History form.

Please ensure the “Reason for use” matches the condition the medication is being taken for in the Medical History or Adverse Event form (unless the medication is used as prophylaxis).

Start Date Enter the corresponding date of onset (dd MMM yyyy). For medications started prior to study start and exact date is unknown, enter ‘UN’ for Day and ‘UNK’ for the month.

If the Start Year and Month are equal to or after the Screening Visit Date, a complete date is expected and an Unknown Start Day will be queried.

End Date If medication/treatment has stopped, enter a complete date. A partial/unknown date is not allowed.

Select the Ongoing radio button if the subject continues to receive the medication/treatment and leave the End Date blank.

If medication/treatment was ongoing and stops, enter the End Date and deselect the Ongoing radio button.




Dose Provide the dose per administration in numeric format. If subject takes different doses at different times, record as separate entries. Verify that Start and Stop Dates of consecutive records for the same medication do

not overlap. For some medications, where there is a variable dose across the regimen, the highest dose across the entire date range can be entered rather than separate records for each day’s dose, e.g. z-pak.

Units Utilize the drop down list to select one of the following:

Cubic centimeter Milliliter Milligram Microgram Grain Gram Milliequivalent Ounce Tablet Capsule Suppository Teaspoon Tablespoon Ampule Bottle Drops Liter Patch Vial Spray Kilogram Milligram/Kilogram/Minute Microgram/Kilogram/Minute Milligram/Kilogram/Hour Microgram/Kilogram/Hour Milligram/Kilogram Milliliter/Kilogram Gram/Kilogram

Route Utilize the drop down list to select one of the following: Intravenous Subcutaneous Per rectum Inhaled Intramuscular Per vaginam Sublingual Topical Per OS - by mouth Therapy Other

If “Other” is selected: If no other value is appropriate, enter the reason as text. A response longer than 50 characters, including spaces, will result in an error message.




Frequency Utilize the drop down list to select one of the following: Once a day Twice a day Three times a day Four times a day As needed Single dose Other If “Other” is selected: If no other value is appropriate, enter the reason as text. A response longer than 50 characters, including spaces, will result in an error message.

Please note that:

Whenever data are entered in the field: Medication/Therapy Name on Concomitant Medication CRF page then field: AECMNO ( Adverse Event, CM No) will be auto-populated on AE form along with corresponding logline number.

Example pasted below:

Data entered in Concomitant Medications form is:



Now when we access this AE CM No field on Adverse Events form, then we can have the data as:

On the AE CRF page, the same conmed will appear automatically under the field CM No, with the same consecutive number of the conmed as present at the CONMED page.

If you require to have multiple corresponding CMs on same AE Logline record, the CM line number can be entered as follows: 2, 3, 15, 25,but a Non-Conformant query will populate as field is set up to only capture one CM. These Non-Conformant queries do not need to be addressed.

7.6. Demography


Date of Birth Full date of birth is expected.A partial/unknown date is not allowed except if restricted by regulatory privacy restrictions. If complete date of birth cannot be obtained due to regulatory restrictions, enter 01 in the day field, select month from the drop down list and enter the year

Gender Utilize the drop down list to select one of the following: Male Female

Ethnicity Utilize the drop down list to select one of the following: Hispanic or Latino Not Hispanic or Latino




Race Select the most appropriate radio button. If the subject is mixed race or does not fit within any category listed, select Other: o American Indian or Alaska Native o Asian o Black or African American o Native Hawaiian or Pacific Islander o White o Other

Save the form.

If “Other” is selected: Type the subject’s race(s) in the free text field. A response longer than 200 characters, including spaces, will result in an error message.

If “Asian” is selected: Please indicate if the subject is of Japanese descent by selecting “Yes” or “No”

If “Yes” is selected to indicate the subject is of Japanese descent: Select one of these choices: First generation, Second generation or Third generation.

Age This field is calculated by RAVE. If the Age is incorrect, please review the Date of Birth and the Date of Informed Consent and correct as needed.

Age unit This fields is pre-populated with Months as age unit

Birth Weight Type the numeric dose into this field to record measured subject’s weight, fixed unit is Kg.



7.7. DNA Sample


DNA sample (subject)

Was sample collected?

If No o Select the No radio button if sample was not collected

If Yes o Select the Yes Radio button if the subject DNA sample was collected o Also enter:

date collected time collected

Maternal genetic sample





Paternal genetic sample





7.8. End of Treatment


Did the subject complete at least 18 months of treatment?

Enter yes or no

Date of last treatment (dd-mmm-yyyy)

Full date is expected



If subject did not complete at least 18 months of treatment,

include reason:

Utilize the drop down list to select one of the following: Disease progression Adverse event (enter correspondending AE number) Death Subject withdrawal Protocol deviation/Non-compliance (specify) Lost to follow up (Date of last contact) Investigator request Sponsor study termination Other If “Other” is selected: Type the reason in the free text field. A response longer than 200 characters, including spaces, will result in an error message.

If patient is ending treatment due to transition to commercial product or compassionate use then select other and specify ‘Transition to ‘commercial product’ or ‘compassionate use’ accordingly.

If “death” is chosen and/or “visit date” form on the “follow up/early withdrawal” visit is marked as not done. All other forms on the “follow up/early withdrawal” visit are not to be completed. CRA should request DM to have them inactivated.

7.9. Anthropometrics (See protocol flow chart for Schedule of Assessments)

For subjects ≤2 years of age at the time of examination collect recumbent length, for subjects >2 years of age at the time of examination collect height.


Date of Assessment Enter the date (dd MMM yyyy) that these measurements were taken. A partial/unknown date is not allowed.

Recumbent length (height)

Enter only numbers with one decimal point, e.g. 124.6. Height must be recorded in centimeters. Values <30 or >200 will result in a query.

Weight Weight must be recorded in kilograms. 2 decimal points are allowed, e.g. 5.24 kg Values <2 or >100 will result in a query.

Abdominal circumference

Enter only numbers with one decimal point, e.g. 24.6. abdominal circumference must be recorded in centimeters. Values <10 or >100 will result in a query.

Head circumference Enter only numbers with one decimal point, e.g. 24.6. Head circumference must be recorded in centimeters. Values <20 or >70 will result in a query.




Mid-upper arm circumference

Enter only numbers with one decimal point, e.g. 24.6. Mid-upper arm circumference must be recorded in centimeters. Values <5 or >50 will result in a query.

7.10. Inclusion/Exclusion


Did the subject meet all eligibility criteria?

If No o Select the No radio button if the subject did not meet all protocol specified

eligibility requirements.

If Yes o Select the Yes Radio button if the subject met all eligibility requirements. o Also enter:

o Inclusion Criteria(check all that the patient meets) o Exclusion Criteria (check all that the patient does not meet) o Date of Enrollment (dd-mon-yyyy)

Date of Enrollment Enter the date (dd MMM yyyy) when Subject was enrolled. A partial/unknown date is not allowed.



7.11. Informed Consent


Date of Informed Consent

Enter the date (dd MMM yyyy) when Subject parents or legal guardian signed Informed Consent. A partial/unknown date is not allowed.

Was consent to photo release obtained as part of the main consent form?

Select the Yes or No radio button

Was maternal consent for genetic samples obtained?


If yes is selected then enter also date of maternal consent. A partial/unknown date is not allowed.

Was paternal consent for genetic samples obtained?


If yes is selected then enter also date of maternal consent. A partial/unknown date is not allowed.

Protocol Version Enrolled under

Select the protocol version from drop down list:

Original Protocol

Amendment 1

Amendment 2 Amendment 3 Amendment 4

7.11.1. Autopsy Consent

Was autopsy consent obtained?


“Yes” or “No” should only be chosen if the patient passes away.

If patient completes the study or discontinue the study for any other reason besides death, please select “Not Applicable”

f Yes, Date of autopsy consent (dd-mon-yyyy)

If yes is selected then enter also date of autopsy consent. A partial/unknown date is not allowed.



7.12. Survival log

This form should be completed for all the patients. DM will query if page is incomplete or blank.

7.13. Clinical laboratory Tests-LAL Enzyme (Screening)

If laboratory sample(s) were collected but were not received/analyzed by the laboratory, enter the

samples as collected on the laboratory assessments form.


Was a PBMC sample collected?

If No

Select the No radio button if the laboratory sample that is utilized for this test was not collected from the subject at this visit.

If Yes

Select the Yes radio button if the laboratory sample that is utilized for this test was collected at this visit.

Also enter:

o Time Collected

o Date Collected

o Results




Was a dried blood spot sample collected?

If No

Select the No radio button if the laboratory sample that is utilized for this test was not collected from the subject at this visit.

If Yes

Select the Yes radio button if the laboratory sample that is utilized for this test was collected at this visit.

Also enter:

Date Collected Time collected

7.14. Coagulation Panel (Screening, Wk 0, Wk 1, Wk 2, Wk 3, Wk 4, Wk 6, Wk 8, Wk 10, Wk 12, Wk 16, Wk 20, Wk24, every 2 months through Wk 48 and every 3 months thereafter, Wk156, Follow up/Early Withdrawal)

Clinically significant abnormal labs at Screening will be captured in Medical History. Clinically significant abnormal non-Screening labs will be captured as an Adverse Event Lab test required per protocol and performed outside of study visit window are to be entered as

unscheduled visit and should be reported as AE if clinically significant Enter Date Collected on all lab pages and Results, save the form, and then select the Local Lab

Name from the drop-down box. If Lab Name is not present, please ensure local lab normal ranges have been submitted to CRA


Not done Select the No radio button if the laboratory samples that is utilized for this test was not collected from the subject at this visit

Date Collected Enter the date samples was collected. A partial/unknown date is not allowed.

Enter Date Collected on all lab pages and Results, save the form, and then select the Lab Name from the drop-down box. If Lab Name is not present, please ensure local lab normal ranges have been submitted to CRA

Time collected Enter the time of samples collection in 24 hours format.

Lab-Age Enter the subject age expressed in days

Lab test If any Lab Tests are not completed, provide information by selection the radio button. Otherwise enter data for each test

PT

PTT



7.15. Hematology (Screening, Wk 0, Wk 1, Wk 2, Wk 3, Wk 4, Wk 6, Wk 8, Wk 10, Wk 12, Wk 16, Wk 20, Wk24, every 2 months through Wk 48 and every 3 months thereafter, Wk156, Follow up/Early Withdrawal )

Enter Date Collected on all lab pages and Results, save the form, and then select the Local Lab Name from the drop-down box. If Lab Name is not present, please ensure local lab normal ranges have been submitted to CRA

Lab test required per protocol and performed outside of study visit window are to be entered as unscheduled visit and should be reported as AE if clinically significant

INR

Fecal Occult Blood (numbers and text allowed)





Time collected Enter the time of samples collection in 24 hours format


Lab test If any Lab Tests are not completed, provide information by selecting the applicable “not Done” radio button.

For lab tests performed enter informaiton in the data field

WBC

RBC

HGB

HCT

MCV

MCH

MCHC

Platelet Count

Neutrophils (absolute value)

Neutrophils % results



7.16. Chemistry (Screening, Wk 0, Wk 1, Wk 2, Wk 3, Wk 4, Wk 6, Wk 8, Wk 10, Wk 12, Wk 16, Wk 20, Wk24, every 2 months through Wk 48 and every 3 months thereafter, Wk156, Follow up/Early Withdrawal)



Lymphocytes (absolute value)

Lymphocytes % results

Monocytes (absolute value)

Monocytes % results

Eosinophils (absolute value)

Eosinophils % results

Basophils (absolute value)

Basophils % results

Cell/Morph (Absolute value entered only)

Cell/Morph % Results








Glucose

Urea Nitrogen

Creatinine

Sodium



7.17. LFT (Screening, Wk 0, Wk 1, Wk 2, Wk 3, Wk 4, Wk 6, Wk 8, Wk 10, Wk 12, Wk 16, Wk 20, Wk24, every 2 months through Wk 48 and every 3 months thereafter, Wk156, Follow up/Early Withdrawal)



Potassium

Chloride

Calcium Total

Magnesium

Phosphorus

Total Protein

Lactate Dehydrogenase

Ferritin

High Sensitivity C Reactive Protein (xxxx.xxx) (To be completed for numeric results)

High Sensitivity C Reactive Protein (to be completed for results not only numeric, i.e. <1)








If any specific Lab Tests are not completed, provide this information by selecting the name of the Lab Test from the drop down list and checking the Not Done box.



7.18. Urinalysis (Screening, Wk 0, Wk 1, Wk 2, Wk 3, Wk 4, Wk 6, Wk 8, Wk 10, Wk 12, Wk 16, Wk 20, Wk24, every 2 months through Wk 48 and every 3 months thereafter, Wk156, Follow up/Early Withdrawal)



*Please note that:

GGT’ that is listed in the results section is the same as GGTP listed in the dropdown list.

For Ferritin and CRP- drop down list is not available. If DM has queried the result, please respond that the test was not done. No further action is needed.That response will be acceptable by Data Management and query will be closed.


AST/SGOT

ALT/SGPT

Alkaline Phosphatase

GGT

Albumin

Bilirubin (Direct) (xxxx.xxx) (To be completed for numeric results)

Bilirubin (Direct) (to be completed for results not only numeric, i.e. <1)

Bilirubin (Indirect) (xxxx.xxx) (To be completed for numeric results)

Bilirubin (Indirect) (to be completed for results not only numeric, i.e. <1)

Bilirubin (Total) (xxxx.xxx) (To be completed for numeric results)

Bilirubin (Total) (to be completed for results not only numeric, i.e. <1)





7.19. Lipid Panel (Screening, Wk 0, Wk 1, Wk 2, Wk 3, Wk 4, Wk 6, Wk 8, Wk 10, Wk 12, Wk 16, Wk 20, Wk24, every 2 months through Wk 48 and every 3 months thereafter, Wk156, Follow up/Early Withdrawal)

Clinically significant abnormal labs at Screening will be captured in Medical History. Clinically significant abnormal non-Screening labs will be captured as an Adverse Event





Urinalysis results Enter the overall result of the urinalysis by selecting radio button:

Normal Abnormal (not clinically significant) Abnormal (clinically significant)



pH

Glucose

Ketones

Protein

Blood

Nitrite

Leukocites

Formed cellular elements

Casts

Bacteria

Yeast

Parasites

RBC

WBC





7.20. Exploratory biomarkers (Screening, Wk2, Wk 8, Wk 12, Wk 16, Wk24, every 6 months after Wk 24, Follow up/Early Withdrawal)

Lab test required per protocol and performed outside of study visit window are to be entered as unscheduled visit.

CRF page at week 156 contains Exploaratory biomarkers folder but collection is not required at week 156. Please respond NOT DONE when you open the page







Lab test If any Lab Tests are not completed, provide information by selection the radio button.

Total Cholesterol

Triglyceride

HDL

LDL



Date sample Collected

Enter the date samples was collected. A partial/unknown date is not allowed.



7.21. ADA (Screening, Wk 2, Wk 4, Wk8, Wk 12, Wk 16, Wk20, Wk24, every 3 months after Wk 24, Wk156, Follow-up/Early Withdrawal)

Lab test required per protocol and performed outside of study visit window are to be entered as unscheduled visit

7.22. LALD Disease History - Screening


Date of Diagnosis This is the initial date of diagnosis prior to study entry. Do not enter dates of diagnostic tests done as part of the study. If multiple diagnostic tests were done, the date here should be for the earliest performed.

Method of diagnosis Check box for following (select all that apply): Enzyme activity Genetic Sequencing Other

Once one method of diagnosis is selected the corresponding page will appear, please refer to correspondent forms instructions below. More than one method of diagnosis can be selected.

If “Other” is selected: If no other value is appropriate, enter the reason as text. A response longer than 50 characters, including spaces, will result in an error message.

7.23. LALD Disease History Enzyme Activity - Screening


Enzyme type Select the enzyme test type:

DBS PBMC

Name of the lab Enter the name of laboratory that performed the test, then also enter: Result Unit Other

Time sample collected Enter the time sample was collected



Date sample Collected

Enter the date samples was collected. A partial/unknown date is not allowed.

Time sample collected Enter the time sample was collected




Reference ranges

7.24. LALD Disease History Genetic Sequencing


Specimen type Select the specimen type:

Cell culture

Other

Name of the lab Enter the name of laboratory that performed the test, then also enter: Exon DNA sequence variation Effect

7.25. LALD Disease History Other


Other Enter type of disease test done

Name of the lab Enter the name of laboratory that performed the test, then also enter: Results Unit

7.26. Liver Biopsy (Wk48, Wk96, Wk144)

Liver biopsy must be done at week 144. Week 156 is optional and can be marked as Not Done. However, if for any reason week 144 assessment was not done then ensure week 156 assessment gets done.


Was liver biopsy performed?

If No o Select the No radio button if a liver biopsy was not performed during the visit. o Save the form. o Also enter: o If No, specify reason by selecting applicable reason from the dropdown

codelist o Medically contraindicated o Other, specify If ‘Other, specify’ is selected, type the reason into this field. A

response longer than 200 characters, including spaces, will result in an error message.




If Yes o Select the Yes radio button if a liver biopsy was performed during the visit. o Save the form.

Date liver biopsy performed

Enter a complete date. A partial/unknown date is not allowed.

What method was used to perform liver biopsy?

o Select the method used:

o Percutaneous o Other, specify If ‘Other, specify’ is selected, type the reason into this field. A

response longer than 200 characters, including spaces, will result in an error message

7.27. Medical History Notes: LAL Deficiency related findings and out of range lab values at screening should be recorded as medical history


How many nights has the subject stayed overnight in the hospital in the past 30 days prior to informed consent.

Insert number of days spent in hospital by the patient in the 30 days before screening

Does the subject have any previous relevant medical conditions (including surgery and clinically significant examination abnormalities) at Screening?

If No o Select the No radio button if the subject does not have any significant medical

history, including surgeries. o If the answer is No, the Medical History form will not display and you will

move to the LALD Disease History form.

If Yes o Select the Yes radio button if subject has any relevant medical history

including surgeries. o Also enter:

o Condition or surgery o Severity o Onset date o End Date o Is condition ongoing at the time of informed consent o In the opinion of the Investigator, is this a sign or symptom of LALD?

If more than one condition/surgery is to be reported select “add new log line” to create a new medical history

Condition or surgery Type in the condition/surgery. A response longer than 200 characters, including spaces, will result in an error message. •LAL Deficiency related findings and out of range lab values at screening should be recorded. •Record Screening Clinically Significant Abnormal ECG findings.




•Record Screening Clinically Significant Abnormal Physical Examination findings.

Severity Enter the Severity utilizing the drop down.

Mild Moderate Severe Unknown Not applicable

Onset date Enter the corresponding date of onset. A partial/unknown day and month are

allowed. For unknown day enter “UN”, for unknown month enter “UNK”.

If the onset date is after the infusion start date, please enter as an Adverse Event, not Medical History.

End date Enter the corresponding date of end. A partial/unknown day and month are allowed. For unknown day enter “UN”, for unknown month enter “UNK”.

Is condition ongoing at the time of informed consent

This status should be determined during Screening and should not be updated during the study.

In the opinion of the Investigator, is this a sign or symptom of LALD?

If recorded condition is considered LAL disease related symptom, check Yes, if not, check No.



7.28. Denver II (Screening, Wk 24, Wk48, Wk72, Wk96, Wk120, Wk144, Follow up/Early Withdrawal, Unscheduled)

CRF page at week 156 contains Denver II folder but collection is not required at week 156. Please respond NO when you open the page.


Was the Denver II Developmental Screening test administered?

If No o Select the No radio button if the Denver II test was not administered at this

visit o If the answer is No, the the Denver II test form will not display

If Yes o Select the Yes radio button if subject the Denver II test was administered at

this visit. o Also enter:

o Date of administration o Time of administration o Name of administrator o Category

o For each category also enter o Number of cautions o Number of delays o Number of refusals

o Overall results

Date of administration Enter a complete date. A partial/unknown date is not allowed.

Time of administration Enter a complete time. A unknown time is not allowed.

Name of administrator Name of administrator must be entered

Category This fields are already populated with list of categories to be assesed o Gross Motor o Language o Fine motor adaptive o Personal-social

For each category enter the numbers of cautions/delays/refusals on the appropriate fields.

Number of cautions Enter the number of cautions. If no cautions were recorded please enter 0. blank fields will prompt a query to be issued

Number of Delays Enter the number of delays. If no delays were recorded please enter 0. Blank fields will prompt a query to be issued

Number of refusals Enter the number of refusals. If no delays were recorded please enter 0. Blank fields will prompt a query to be issued

Overall Result Select from drop down list: o Normal o Suspect o Untestable



7.29. Physical Examination (Screening, Wk3, Wk9, Wk15, Wk20, Wk24, Wk36, Wk48, Wk60, Wk72, Wk84, Wk96, Wk108, Wk120, Wk132, Wk144, Wk156, Follow up/Early Withdrawal, Unscheduled)

Please document all relevant baseline physical exam findings on the Medical History page. After the baseline physical exam, abnormal findings that meet the definition of an adverse event should be entered on to the AE page


Was the physical examination performed?

If No o Select the No radio button if the physical examination was not performed at

this visit.

If Yes Select the Yes radio button if subject examination was performed at this visit. o Also enter:

o Date performed o Time performed o Were there any clinical significant findings? o Clinical Assessment of Liver o Clinical Assesment of Spleen

Date performed Enter a complete date. A partial/unknown date is not allowed.

Time performed Enter a complete time (24 hour clock). A partial/unknown time is not allowed.

Were there any clinical significant findings?

At screening, capture all relevant findings on the medical history eCRF (unless the finding is related to protocol procedures or requirements; these findings should be captured on the AE CRF). From enrollment to end of study all abnormal findings that meet the definition of an adverse event should be captured on the AE CRF.

Clinical assessment (Liver and Spleen)

Follow these directions for each of the clinical assessments (liver and spleen).

If Non-Palpable Select the Non-Palpable radio button. No additional entry is needed.

If Palpable Select the Palpable radio button. Also enter:

o o Centimeters below costal margin (one decimal place allowed) o Regularity o Sensitivity



7.30. Physical Examination Lymphadenopathy (Screening, Wk3, Wk9, Wk15, Wk20, Wk24, Wk36, Wk48, Wk60, Wk72, Wk84, Wk96, Wk108, Wk120, Wk132, Wk144, Wk156, Follow up/Early Withdrawal, Unscheduled)


Date of Assessment A partial/unknown date is not allowed.

Was Lymphadenopathy present upon physical exam?

If No • Select the No radio button if no lymphadenopathy was detected at this visit. If No is selected, then no other response is expected to be completed for any locations on this form. If Yes • Select the Yes radio button if lymphadenopathy was detected at this visit. also enter: o Location o Character o If palpable then ensure the Size and Sensitivity is also reported (Size cm) o If non-palpable/Not Done then response to Size and Sensitivity should be left

blank o Sensitivity

Lymphadenopathy Location

This fields are already populated with list of locations to be assesed 1. Cephalic 2. Cervical 3. Clavicular 4. Axillary 5. Inguinal

For each location complete the appropriate fields

Character

Select from drop down list for each location:

Palpable non palpable not done



If Palpable (Size cm)

If palpable, enter size in cm for each location (one decimal place allowed).

If non palpable, leave blank for each location.

Sensitivity

Select from drop down list for each location:

Tender Not tender Not done

7.31. Physical Examination abdominal photograpy (Screening, Wk3, Wk9, Wk15, Wk20, Wk24, Wk36, Wk48, Wk60, Wk72, Wk84, Wk96, Wk108, Wk120, Wk132, Wk144, Wk156, Follow up/Early Withdrawal, Unscheduled)


Was an abdominal photograph taken?

If No o Select the No radio button if no abdominal photograph was taken at this visit. o also specify if

o did not consent o other: Type in the reason. A response longer than 200 characters,

including spaces, will result in an error message.

If Yes Select the Yes radio button if abdominal photograph was taken at this visit. o Also enter:

o Date performed o Were there any clinical significant findings? o Clinical Assessment of Liver o Clinical Assesment of Spleen

Date taken Enter a complete date. A partial/unknown date is not allowed.

Exam Type Select radio button: Supine front Supine lateral Both front and lateral

Photograph type select radio button: Supine full-length (neck down) supine close-up

upload the photo in the relevant photographe type section:

Supine front full-length supine front close up supine lateral full length supine lateral close up

Ensure that pt face does not appear in the photo. If needed, cut off the face from the photo before uploading



7.32. PK Sampling (Wk0, Wk22, Wk 48)


Not done Check the field if PK sample was not taken at the visit, all other fields can be left blank

Date sample collected Enter the date that all or a majority of the samples were collected. A partial/unknown date is not allowed.

Was blood sample collected for PK Blood Analysis?

Follow the guidelines below for each Timepoint.

If No o Select the No radio button if the PK sample was not collected from the

subject.

If Yes o Select the Yes radio button if the PK sample was collected. o Also enter:

o Check if date same as above o date collected (if different from above) o Time Collected

7.33. Family Medical History


Does/did the subject haveother family members with LALD (that was confirmed by LAL enzyme or genetic testing)?

If No o Select the No radio button if the subject has never had other family members

with LALD. o Save the form.

If Yes Select the Yes radio button if subject has other family members with LALD o Also enter:

o Number of family members o Relationship o Gender o Relevant History o Status

If yes, number of family members

Enter a whole number value, e.g. 1, 2, 4. Count both living and deceased family members.

Relationship Select from the drop down: o Brother o Sister




o Mother o Father o Aunt o Uncle o Grandmother o Grandfather o Cousin

Gender Select from the drop down: o Male o Female

Relevant History Check each appropriate checkbox: abdominal distension Adrenal calcification Angina Ascites Cardiovasculare Disease Cerebrovascular Accidents CV Events (MI, Stroke, Arterial Revascularization) Diarrhea Dyslipidemia Elevated Transaminases Encephalopathy Esophageal varices Failure to thrive Gallstones Hepatomegaly LALD Liver Cancer Liver Cirrhosis Liver Disease Liver Fibrosis Lymphadenopathy Portal Hypertension Splenomegaly Steatorrhea Transient ischemic episode Vomiting Other If ‘Other, Specify’ was selected, Relevant History or Cause of death in the

specify text field should be entered. 50 character is limitation.

Status Select from the drop down: Alive Select Alive from the drop down reflective of the family member history as

provided at Screening. Also enter:

o Relevant History

Deceased Select Deceased from the drop down reflective of the family member history as

provided at Screening. Also enter:




o Relevant History o If Deceased, age at time of death o If Deceased, primary cause of death

If Deceased, age at time of death

Enter in years using only numbers without decimals place.

If Deceased, primary cause of death

Select the one primary cause of death, if known. Check only one:

Cardiovascular Disease Cerebrovascular Accident(s) LALD Liver Cirrhosis Liver Failure Malnutrition Other, specify

Do you need to enter data for another sibling?

If yes, enter data on the Family Medical History form that will be created after your enter “yes”

7.34. Study Completion


Did the subject complete the study?

A subject is considered a completer if they complete 18 months of study treatment and complete the follow-up visit. A screen failure subject is not considered a completer

Date of Study Completion/Early Termination/Screen Failure

A partial/unknown date is not allowed.

This date should correspond to the last study visit/assessment date: o Enrolled subjects: this would be the date of the follow up visit o Screen Failed subjects: this would be the date the subject was determined to

be a screen failure o For subjects that early terminated, this would be the date of the last

assessment performed on study. o For subjects that withdrew consent, this would be the date they formally

withdrew consent. This is not necessarily the last day of treatment (although in some cases it may be). Ensure the end of treatment is documented on the End of Treatment page. *Please note: Study completion date should be the date of the last study procedure at the follow up visit. It should NOT be the last treatment visit date.




If subject did not complete the study, indicate reason

If Screen Failure Select the Screen Failure radio button if the subject was screened but not enrolled. Indicate why the patient screen failed by selecting either:

o Patient withdrew consent o Entry criterion

Other

If Disease Progression o Select the Disease Progression radio button. A corresponding Adverse Event

entry is not required.

If Adverse Event o Select the Adverse Event radio button and also enter Adverse Event

Number(s)

Ensure the Adverse Event is recorded on the Adverse Event form with an IMP Action Taken of “Study drug permanently discontinued”.

If Death o Select the Death radio button. o Save the form. o Also enter:

o Date of Death o was an autopsy performed and, if yes, specify findings

o Ensure the cause of death is recorded on the Adverse Event form with an Outcome of “Fatal.”

If Subject Withdrawal o Select the subject Withdrawal by radio button if the subject chose to end

participation after enrollment. If the subject was not enrolled, please select “Screen Failure” and then specify that the patient withdrew consent

If Protocol Deviation/Non-Compliance o Select the Protocol Deviation/Non-Compliance radio button. o Also enter:

o Protocol Deviation/Non-Compliance, specify

If Lost to Follow-up o Select the Lost to Follow-up radio button. o Also enter:

o Date of Last Contact. Date of last contact is the last contact attempt that was made to try to reach the subject. It is not the last assessment on study.

If Investigator request o Select the Investigator request radio button.

Also enter the reason as text. If a similar selection is already available on this form, a query will be issued.

If Sponsor Study Termination o Select the Sponsor Study Termination radio button if the Sponsor terminates

the study early. Only select this option if you are directed to by study communications




If none of the selections is applicable

o Select the Other radio button. o Also enter:

o If no other value is appropriate, enter the reason as text. If a similar selection is already available on this form, a query will be issued.

7.35. Transfusion Field/Question Instructions

Not done Mark in case no transfusion have been performed to the subject during the study.

Date of transfusion A partial/unknown date is not allowed.

Type Select the correct type of translation radio button:

o Packed red blood cells o plasma o Platelets o White blood cells o Other, specify

Reason for transfusion

Enter the medical reason for the transfusion

Amount, Unit Enter the amount of transfusion and relevant Unit

7.36. Enteral food Intake log Field/Question Instructions

Dietary type Select appropriate radio button:

o Total Parenteral Nutrition (TPN) o Partial Parenteral Nutrition (PPN) o Breastfed o Specialized formula, Oral or tube-fed (Medium Chain Triglyceride or other) o Low or no cholesterol oral feeds o Unrestricted diet oral feeds o Other

In case other is selected, enter details on “specify”

Start date A partial/unknown date is not allowed, however if the month is truly unknown, please select UNK from the drop down list.

Stop date A partial/unknown date is not allowed, however if the month is truly unknown, please select UNK from the drop down list.



Field/Question Instructions Ongoing Select if the dietary type is ongoing. In case dietary has changed, enter stop date

and add a new Log line

7.37. IMP Admin Field/Questi

on Instructions

Was infusion administered?

If No o Select the No radio button if infusion was not administered at this visit. o Save the form.

If Yes Select the Yes radio button if infusion was administered at this visit. o Also enter:

o Date of Infusion o Target Dose o Frequency o Weight-used to calculate dose o Total Volume of Infusion o Start Time of Infusion o End Time of Infusion o Number of vials o IMP lot number

Date of Infusion

Enter a complete date. A partial/unknown date is not allowed.

Has there been any change in the planned IMP administration since last visit

Applicable only after Week 0 visit. Respond to this question and all sub questions in relation to the prior infusion administered. For example, if this is the fourth infusion, you would be comparing it to the third infusion. If Yes Select the Yes radio button if there were changes since last visit. o Also enter:

o Reason for IMP administration change o Dose o Frequency o Rate

If Yes: Reason for IMP administration change

Select the applicable radio button: Clinical response – select this reason if the reason for the dose change was because

the subject met dose escalation criteria (see protocol section 3.1.1) Significant progression select this reason for accelerated dose changes in exceptional

cases with a particularly severe clinical presentation or evidence of rapid or substantial clinical deterioration, including but not limited to inadequate weight gain, ongoing weight loss deemed to be related to LAL Deficiency or a symptomatic progression of liver disease

Intolerance Other, specify

If Yes: Dose Select the applicable radio button: 1- Increase – select this reason if the dose being given at this infusion is higher than the previous dose 2 – Decrease – select this reason if the dose being given at this infusion is lower than the previous dose 3- No change



Field/Question

Instructions

If Yes: Frequency

Select the applicable radio button:

Increased Decreased No change

If Yes: Rate Select the applicable radio button:

Increased Decreased No change

Target Dose Select the applicable radio button:

1 mg/kg 3 mg/kg 5 mg/kg 7.5 mg/kg

Frequency Select the applicable radio button:

qw - every week qow - every other week

Weight-used to calculate dose

Enter the weight utilized to calculate the dose. If subject’s weight cannot reliably be obtained on the morning of the infusion then the subject’s most recent weight measurement within 7 days, rounded to the nearest 0.1 kg, will be used for calculating the volume of study drug to be withdrawn from the vial(s) to prepare the infusion. Enter only numbers with one decimal place, e.g., 28.6, 71.2. The Weight must be recorded in kg and rounded to the nearest 0.1 kg.

Total Volume of Infusion

Enter only whole numbers with no decimal points, e.g., 100. This is the volume of the prepared bag used for the infusion, recorded in mL.

Start Time of Infusion

Enter a complete date in 24 hour clock.

End Time of Infusion

Enter a complete date in 24 hour clock. Enter the time when the infusion bag was empty before the sodium chloride flush.

Number of vials

Enter the total number of IMP vials administered

IMP lot number

Enter IMP lot number as reported on IMP box – if there are multiple vials/lot numbers, enter each lot number and number of vials in a separate log line

7.38. IMP Admin Continued

Infusion rate o Enter all infusion rates, with corresponding start and end times, from start of first infusion rate to end of last infusion rate:

o Infusion Rate – for interruptions enter a rate of 0ml/hr



o Start Time at this Rate o End Time at this Rate

o Reason for rate change to be entered Check applicable radio button: IAR Other AE Administration issue N/A – Initial rate Other, specify

o If Other, specify into the free text field

o What was the modification to the rate? Check applicable radio button: Increased Decrease Interruption N/A – Initial rate

Click Add a new log line (after completing entry in the first row) to add another row. Enter one Infusion Rate per row.

Infusion Rate Enter only numbers with one decimal place, e.g. 50.0. This rate must be recorded in mL/hr.

Start time at this rate Enter a complete time using the 24 hour clock.

End Time at this Rate Enter a complete time using the 24 hour clock.

End Time of the last infusion rate is the time at the completion of the IMP (when the bag is empty), before the sodium chloride flush.

Was the full planned volume of IMP administered?

If No o Select the No radio button if subject did not receive the entire volume of the

infusion bag. o Also enter:

o Reason

1- Infusion discontinued – select this if the infusion was interrupted and never restarted at this visit.

2 – Other, Specify.

If Yes o Select the Yes radio button if “Total Volume of Infusion Bag” was administered

to the subject.CALCULATED Total Volume of IMP actually administered (mL):

This field will autopopulate

When was the Saline Flush Administration

Start time Enter a complete time using the 24 hour clock. Stop time Enter a complete time using the 24 hour clock.

What is the next planned dose frequency

Check applicable radio button: qw qow



7.39. Visit Date


Visit Date Enter the actual date of the subject’s site visit. A partial/unknown date is not allowed.

Utilize the earliest date if the subject returns more than once for the same visit.

Visit Date is required at Screening.

Visit Not Done Leave blank if the visit was done. If Not Done, select reason from drop down list:

o Infusion withheld due to IAR o Infusion withheld due to other AE o Non-compliance o Administrative issue o Subject transitioned to qow dosing o Other, specify

Check the Visit Not Done box if the subject missed the entire study visit. All forms within this visit should be marked “Not Done”

If this box is checked in error, uncheck “Not Done”, enter the Visit Date using the edit function, and save the form. The visit forms will be available for data entry.

7.40. Vital Signs Note: If a clinically significant change occurs, as determined by the Investigator, please record on the Adverse Event form.

On dosing days, vital signs will be recorded pre-infusion ,every 15 (±5) minutes during the infusion and every 30 (±10) minutes from 0 to 4 hours after the end of the infusion.

After a subject has successfully completed at least 1 year of treatment with no occurrence of moderate-to-severe IARs, the post infusion period for vital sign monitoring may be shortened from 4 hours to 2 hours.

End of Infusion is the time when the bag is empty, before sodium chloride flush. Throughout the study, additional readings may be taken at the discretion of the Investigator.


Screening, Follow up/Early withdrawal

Vital Signs Page

Enter data into every field section: Date of Assessment Time of Assessment Body Temperature Pulse Rate Respiratory Rate Systolic Blood Pressure Diastolic blood pressure

Pre Infusion

Vital Signs Pre Infusion Check the “Not Done “ box if the vital signs were not done. If this box is checked, do NOT enter data into any other field on this form. If vital signs were collected, enter data into every field under the “All Vital Signs Forms” section: Date of Assessment Time of Assessment Body Temperature




Pulse Rate Respiratory Rate Systolic Blood Pressure Diastolic blood pressure

During Infusion

Vital Signs During Infusion/

Vital Signs During Infusion Additional

Check the “Not Done “ box if the vital signs were required for the timepoint, but were not done and vital signs were taken at another timepoint at this visit. If this box is checked, do not enter data into any other field in this row. If vital signs were collected, enter data into every field under the “All Vital Signs Forms” section: Date of Assessment Time of Assessment Body Temperature Pulse Rate Respiratory Rate Systolic Blood Pressure Diastolic blood pressure

Post Infusion

Vital Signs Post Infusion Check the “Not Done “ box if the vital signs were required for the timepoint, but were not done and vital signs were taken at another timepoint at this visit. If this box is checked, do not enter data into any other field in this row. If vital signs were collected, enter data into every field under the “All Vital Signs Forms” section: Date of Assessment Time of Assessment Body Temperature Pulse Rate Respiratory Rate Systolic Blood Pressure Diastolic blood pressure

Not Applicable Week 52 and greater Timepoints 1 through 4 are required. If vital signs were not done, check the Not

Done box. Timepoints 5, 6, 7 and 8 may not be required. After a year of treatment with no

IARs, the post-infusion monitoring period may be shortened from 4 hours to 2 hours. If vitals were not required to be taken, check Not Applicable and do not enter data into any other field on this row. If vital signs should have been collected, but were not, check the Not Done box.



Date of Assessment Enter the actual date of the assessment. A partial/unknown date is not allowed.

Time of Assessment Enter a complete time using the 24 hour clock. An unknown time is NOT allowed.

Values outside the ranges listed below will result in a query: Predose: if time is on or after the study drug infusion start time Dosing: if time is prior to study drug infusion time Postdose: If time is prior to study drug infusion end time Postdose: if time is not between 20 and 40 minutes after the previous vital sign

time

Body Temperature Enter only numbers with one decimal place, e.g., 37.2. Temperature must be recorded in degrees Celsius.

Values outside the ranges (<35 or >45) will result in a query:

Pulse Rate Enter only a three digit whole number, e.g. 76, 102. Pulse rate must be recorded in beats per minute.

Values outside the ranges (<50 or >200) will result in a query: Respiratory Rate Enter only a two digit whole number, e.g. 17, 29. Respiratory rate must be recorded

in breaths per minute.

Values outside the ranges (<20 or >70) will result in a query:

Systolic/Diastolic Blood Pressure

Enter the three digit systolic number in the first field and the three digit diastolic number in the second field. Blood pressure should be recorded in mmHg.

Values outside the Systolic ranges (<30 or >150) will result in a query. Values outside the Diastolic ranges (<20 or >130) will result in a query.

7.39 Concomitant Procedures

Concomitant Procedure YN – Once Yes is selected, the Concomitant Procedure page will be available for entry.

All study related procedures ( liver biopsy, MRI, EGD etc. ) should not be recorded in this folder ( concomitant procedures). They are recorded in the separate study folder applicable for each procedures.

Please note that filed ‘’Major findings’’ has a length of 200 characters only.



8.0 Investigator Signature

The Primary Investigator or a Sub-Investigator (designated on Form 1572) must review all of the data for each subject at their site and provide their acknowledgement that the data are correct and accurate. The PI/sub-PI will be granted permissions in the database to sign completed electronic casebooks and each SAE.

The form is signed by entering the username and password of the signer.

electronic case report form completion guidelines · lal-cl08 ecrf completion guidelines version...

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